Pictolysin-III, a Hemorrhagic Type-III Metalloproteinase Isolated from Bothrops pictus (Serpentes: Viperidae) Venom, Reduces Mitochondrial Respiration and Induces Cytokine Secretion in Epithelial and Stromal Cell Lines

From the venom of the Bothrops pictus snake, an endemic species from Peru, we recently have described toxins that inhibited platelet aggregation and cancer cell migration. In this work, we characterize a novel P-III class snake venom metalloproteinase, called pictolysin-III (Pic-III). It is a 62 kDa proteinase that hydrolyzes dimethyl casein, azocasein, gelatin, fibrinogen, and fibrin. The cations Mg2+ and Ca2+ enhanced its enzymatic activity, whereas Zn2+ inhibited it. In addition, EDTA and marimastat were also effective inhibitors. The amino acid sequence deduced from cDNA shows a multidomain structure that includes a proprotein, metalloproteinase, disintegrin-like, and cysteine-rich domains. Additionally, Pic-III reduces the convulxin- and thrombin-stimulated platelet aggregation and in vivo, it has hemorrhagic activity (DHM = 0.3 µg). In epithelial cell lines (MDA-MB-231 and Caco-2) and RMF-621 fibroblast, it triggers morphological changes that are accompanied by a decrease in mitochondrial respiration, glycolysis, and ATP levels, and an increase in NAD(P)H, mitochondrial ROS, and cytokine secretion. Moreover, Pic-III sensitizes to the cytotoxic BH3 mimetic drug ABT-199 (Venetoclax) in MDA-MB-231 cells. To our knowledge, Pic-III is the first SVMP reported with action on mitochondrial bioenergetics and may offer novel opportunities for promising lead compounds that inhibit platelet aggregation or ECM–cancer-cell interactions.</p

Understanding Planar Ligand-Supported MAu₅ and MAu₆ Cores. Theoretical Survey of [MAu₅(Mes)₅] and [MAu₆(Mes)₆] (M = Cu, Ag, Au; Mes = 2,4,6-Me₃C₆H₂) Under the Planar Superatom Model

The planar superatom model has been applied to the case of planar ligand-supported MAu₅ and MAu₆ cores, where M = Cu­(I), Ag­(I), and Au­(I), in order to increase the understanding of the electronic structure and bonding properties of planar golden clusters. The study of [Au₅(Mes)₅], [Au₆(Mes)₆], [MAu₅(Mes)₅], and [MAu₆(Mes)₆] has been carried out by using relativistic DFT calculations, which describe the short d¹⁰–d¹⁰ contacts due to the bonding stabilization within the Au_<i>n</i> core in addition to the respective <i>aurophilic</i> phenomena. The results under the planar superatom approach allow us to characterize the electronic structure in all the systems as formally 10 valence electron cores, depicting an overall 1s²1p_{<i>x</i>,<i>y</i>}⁴1d_{<i>xy</i>,<i>x</i>2–<i>y</i>2}⁴ configuration as a result of the ligand–metal interaction. The inclusion of the respective M­(I) closed shell center increases the number of superatomic shells as 1s1p1d → 1s1p1d2s, denoting the interaction between each concentric section. Our results suggest that the MAu<i>_n</i> cores could be conveniently viewed as the combination of concentric structures denoted by [M@Au_<i>n</i>]. In addition, the role of the inclusion of the spin–orbit term into the planar superatom model is discussed

Impacto de la capacitación en el desarrollo de carrera

Tesis (Magíster en Administración de Empresas)Nuestro estudio contempla un marco teórico referido al talento humano, la capacitación y el desarrollo de carrera. Estos tres grandes elementos se presentan por separado por consideraciones más bien didácticas, pero en su utilización práctica en la definición y formulación de estrategias y políticas de Gestión de Recursos Humanos necesariamente deben combinarse la perspectiva del individuo, la de la organización y su enfoque a la carrera y las áreas de acción en la gestión de la carrera. Las preguntas son múltiples y, hasta ahora, el terreno poco explorado. No tenemos evidencia documentada de lo que está sucediendo en nuestras empresas en el sentido de que la capacitación realmente impacte positivamente en el desarrollo de la carrera profesional de los trabajadores, por lo que resulta interesante intentar conocer esta experiencia. Tal inquietud es el motor de nuestro estudio exploratorio, de la experiencia de algunas empresas chilenas, donde hemos querido hacer una primera aproximación al "estado del arte" en nuestro país con respecto al impacto de la capacitación en el desarrollo de la carrera laboral. La importancia de otorgarle un sentido a la capacitación y que no se constituya como un instrumento que se efectúa por obligación. En este sentido, nos referimos a que las empresas no deben considerar el proceso de capacitación como un instrumento de "moda", sino que debe considerarse con la seriedad que merece otorgándole un sentido, es decir, para que una empresa logre a través de la capacitación un impacto positivo en la empresa, es relevante que a ésta se le otorgue una importancia y sentido de largo plazo, siendo la existencia de una política u orientaciones de capacitación dos elementos que permitirán generar procesos de capacitación con un objetivo claro y que permita que no sean inversiones mal hechas. Una alta inversión en capacitación no garantiza que ésta vaya a tener efectos positivos. Esto porque si bien las compañías chilenas han aumentado su nivel de inversión en capacitación, esto no garantiza resultados positivos, puesto que como se mencionó anteriormente se capacita según las necesidades de la empresa sin considerar las necesidades y/o motivaciones del trabajador, lo cual provoca un freno-natural sobre-los efectos- positivos que pudiese tener la capacitación producto de la desmotivación natural del empleado. No siempre la capacitación es sinónimos de desarrollo de carrera. Los esfuerzos tanto de las empresas como individuales por mejorar las competencias a través de capacitaciones no siempre se ven reflejado en el desarrollo de carrera laboral

Survey Of Long d¹⁰–d¹⁰ Metallophilic Contacts in Four-Membered Rings of Ag(I) and Au(I) Supported by Carbene–Pyrazole Mixed Ligands

The interesting case of long intramolecular d¹⁰–d¹⁰ contacts has been studied through [Ag₄L₂]²⁺ and [Au₄L₂]²⁺ (L = 3,5-bis­((<i>N</i>-methylimidazolyl)­methyl)­pyrazole) systems, showing interesting features gained by analysis of the electronic structure and the overall shielding tensor in the molecular domain, in terms of its components. The long intramolecular closed-shell separations are attributed to the population of the bonding, nonbonding, and antibonding combinations of the <i>n</i>s atomic shells in the [M₄]⁴⁺ core, contrasting with that observed in systems with shorter d¹⁰–d¹⁰ distances. This point allows to concludeb that separations shorter then the sum of the van der Waals radii (3.4 Å for Ag–Ag, and 3.2 Å for Au–Au) of the nucleus involved requires a net bonding population between <i>n</i>s and <i>n</i>p atomic shells of the d¹⁰ closed-shell centers. Moreover, [Au₄L₂]²⁺ exhibits an increased covalency observed for the enhanced charge-donation due to the stabilization of the <i>n</i>s and destabilization of the (<i>n</i> – 1)­d driven by the relativistic effects. The magnetic response denotes a slight interaction between the closed-shell centers at distances in the range of their sum of van der Waals radii because the observed remote effect (or anisotropic effect) caused by each d¹⁰ nucleus does not influence considerably the neighbor center. The analysis of δ in terms of its components allows to conclude that the [Au₄L₂]²⁺ system exhibits an increased magnetic response due to the increase in the number of the inner-electrons in comparison to [Ag₄L₂]²⁺

iPS cells in the study of PD molecular pathogenesis

Parkinson's disease (PD) is the second most common neurodegenerative disease and its pathogenic mechanisms are poorly understood. The majority of PD cases are sporadic but a number of genes are associated with familial PD. Sporadic and familial PD have many molecular and cellular features in common, suggesting some shared pathogenic mechanisms. Induced pluripotent stem cells (iPSCs) have been derived from patients harboring a range of different mutations of PD-associated genes. PD patient-derived iPSCs have been differentiated into relevant cell types, in particular dopaminergic neurons and used as a model to study PD. In this review, we describe how iPSCs have been used to improve our understanding of the pathogenesis of PD. We describe what cellular and molecular phenotypes have been observed in neurons derived from iPSCs harboring known PD-associated mutations and what common pathways may be involved